Imidazo[1,2-F]pteridines useful as inhibitors of protein kinases

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase, represented by Structural Formula (I): wherein the variables in Structural Formula (I) are as described herein. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

1. A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 Ring A is an imidazole ring wherein the ring is optionally substituted with C 1-6  haloalkyl, halo, NO 2 , —OH, —CN or C 1-6  alkyl; 
 X 1  is —NR 8 — 
 R 1  is H, C 1-10  aliphatic, C 3-10  cycloaliphatic, C 6-10  aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl, wherein said R 1  is optionally substituted with 0-5 J 1 ; 
 Each R 2  and R 3  is independently H, or C 1-3  alkyl; 
 R 4  is H, C 1-10  aliphatic, or C 3-10  cycloaliphatic, wherein said R 4  is optionally substituted with 0-5 J 4 ; 
 R 8  is H, C 1-6  aliphatic, C 3-8  cycloaliphatic, —C(O)R, —C(O)OR, or —C(O)NRR′; 
 Each J 1  is independently C 1-6  haloalkyl, halo, NO 2 , CN, Q, or -Z-Q, or two J 1  taken together can optionally form ═O; 
 Each Z is independently C 1-6  aliphatic in which 0-3—CH 2 — units in said C 1-6  aliphatic are optionally replaced with —NR—, —O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, —S(O)—, or —S(O) 2 —, wherein any non-replaced —CH 2 — units in said C 1-6  aliphatic are optionally substituted with 0-2 J Z ; 
 Each Q is independently H, C 1-6  aliphatic, a 3-8-membered aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S, or an 8-12 membered aromatic or non-aromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N, and S, wherein each Q is independently optionally substituted with 0-5 J Q ; 
 Each J Z  is independently halo, C 1-6  aliphatic, C 3-6  cycloaliphatic, NO 2 , CN, OH, NH 2 , NH(C 1-4  aliphatic), N(C 1-4  aliphatic) 2 , —O(C 1-4  aliphatic), —CO 2 H, —CO 2 (C 1-4  aliphatic), —O(haloC 1-4  aliphatic), or halo(C 1-4  aliphatic); 
 Each J Q , and J 4  is independently -M or -Y-M; 
 Each Y is independently an unsubstituted C 1-6  aliphatic in which 0-3 —CH 2 — units in said C 1-6  aliphatic are optionally replaced with —NR—, —O—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —; 
 Each M is independently H, C 1-6  aliphatic, C 3-6  cycloaliphatic, halo(C 1-4  aliphatic), O(haloC 1-4  aliphatic), 3-6 membered heterocyclyl, halo, NO 2 , CN, OH, OR′, SH, SR′, NH 2 , NHR′, N(R′) 2 , COH, COR′, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CON(R′) 2 , OCOR′, OCONH 2 , OCONHR′, OCON(R′) 2 , NHCOR′, NR′COR′, NHCO 2 R′, NR′CO 2 R′, NHCO 2 H, NR′CO 2 H, NHCONH 2 , NHCONHR′, NHCON(R′) 2 , SO 2 NH 2 , SO 2 NHR′, SO 2 N(R′) 2 , NHSO 2 R′, or NR′SO 2 R′; 
 Each R is independently H or unsubstituted C 1-6  aliphatic; and 
 Each R′ is unsubstituted C 1-6  aliphatic, or two R′ groups, together with the atom to which they are bound, form an unsubstituted 3-8 membered saturated or partially unsaturated monocyclic ring having 0-1 heteroatoms independently selected from O, N, and S. 
 
     
     
       2. The compound of  claim 1 , wherein R 1  is H. 
     
     
       3. The compound of  claim 1 , wherein R 1  is optionally substituted C 1-6  alkyl or C 3-7  cycloalkyl. 
     
     
       4. The compound of  claim 1 , wherein R 1  is H, ethyl, cyclopropyl or cyclopentyl. 
     
     
       5. The compound of  claim 1 , wherein R 1  is phenyl and one substituent at the para position of the phenyl is Q or -Z-Q. 
     
     
       6. The compound of  claim 1 , wherein R 1  is thiophen-2-yl, pyridin-3-yl, pyridin-4-yl, or 6-trifluoromethylpyridin-3-yl. 
     
     
       7. The compound of  claim 1 , wherein each of R 2  and R 3  is C 1-3  alkyl. 
     
     
       8. The compound of  claim 1 , wherein R 4  is C 1-6  aliphatic optionally substituted with 0-5 J 4 . 
     
     
       9. The compound of  claim 1 , wherein R 2  is H and R 3  is C 1-3  alkyl. 
     
     
       10. The compound of  claim 9 , wherein R 3  is ethyl. 
     
     
       11. The compound of  claim 8 , wherein R 4  is C 3-10  cycloaliphatic optionally substituted with 0-5 J 4 . 
     
     
       12. The compound of  claim 11 , wherein R 4  is cyclopentyl. 
     
     
       13. The compound of  claim 1 , wherein R 8  is H or —C(O)OR. 
     
     
       14. The compound of  claim 13 , wherein R 8  is H. 
     
     
       15. The compound of  claim 13 , wherein R 8  is —C(O)OC 1-6  alkyl. 
     
     
       16. The compound of  claim 15 , wherein R 8  is —C(O)OCH 3 . 
     
     
       17. The compound of  claim 1 , wherein R 1  is optionally substituted 5-10 membered heteroaryl. 
     
     
       18. The compound of  claim 17 , wherein R 1  is optionally substituted with 0-3 —O-Q, halo, —C(O)N(R)-Q, or Q, in which each Q in Q, —C(O)N(R)-Q and —O-Q is independently optionally substituted with 0-5 J Q . 
     
     
       19. The compound of  claim 17 , wherein the 5-10 membered heteroaryl represented by R 1  is substituted with —C(O)N(R)-Q and any remaining position with —O-Q, or Q, in which each Q in Q, —C(O)N(R)-Q and —O-Q is independently optionally substituted with 0-5 J Q . 
     
     
       20. The compound of  claim 19 , wherein the Q in —C(O)N(R)-Q is H, C 1-4  aliphatic, C 1-4  haloaliphatic, C 3-7  cycloaliphatic, C 3-7  heterocycloaliphatic, or (C 1-6  alkoxy)C 1-6  alkyl. 
     
     
       21. The compound of  claim 1 , wherein each R 1  is optionally substituted C 6-10  aryl. 
     
     
       22. The compound of  claim 21 , wherein R 1  is optionally substituted with 0-3 —O-Q, halo, —C(O)N(R)-Q, or Q, in which each Q in Q, —C(O)N(R)-Q and —O-Q is independently optionally substituted with 0-5 J Q . 
     
     
       23. The compound of  claim 21 , wherein the C 6-10  aryl represented by R 1  is phenyl optionally substituted at the para position with —C(O)N(R)-Q and any remaining position with —O-Q, halo, or Q, in which each Q in Q, —C(O)N(R)-Q and —O-Q is independently optionally substituted with 0-5 J Q . 
     
     
       24. The compound of  claim 23 , wherein the Q in —C(O)N(R)-Q is H, C 1-4  aliphatic, C 1-4  haloaliphatic, C 3-7  cycloaliphatic, C 3-7  heterocycloaliphatic, or (C 1-6  alkoxy)C 1-6  alkyl. 
     
     
       25. The compound of  claim 24 , wherein Q of —C(O)N(R)-Q is methyl, ethyl, 1-methylpiperidin-4-yl, cyclopropyl, cyclopentyl, 3-furanyl, 3-fluoropyrrolidin-1-yl or 3,3-difluorocyclobutyl. 
     
     
       26. The compound of  claim 24 , wherein the phenyl is optionally substituted at any remaining position with halo, C 1-4  aliphatic, C 1-4  haloaliphatic, C 3-7  cycloaliphatic, C 3-7  heterocycloaliphatic, C 1-6  alkoxy, (C 1-6  alkoxy)C 1-6  alkyl or C 1-6  haloalkoxy. 
     
     
       27. A pharmaceutical composition comprising a compound of any one of  claims 1 ,  13 - 5 ,  6 - 10 , and  8 - 12 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.